The publications resulting from our activities of the past year are listed in the accompanying bibliography. In aggregate, these reports have explored how specific signaling molecules, neuropeptides and catecholamines act as first messengers at specific brain synapses to change the behaviors of post-synaptic follower neurons in ways that encode experience, changing organismic behaviors accordingly. For example, the vasopressinergic neurons of the paraventricular nucleus of the hypothalamus have been shown to project to the locus coeruleus of the brain stem, and to influence the activation of these neurons in response to stress. Another set of synapses, between projections from the retina to the suprachiasmatic nucleus of the hypothalamus, resets circadian phase in response to light, and we have now shown that this depends on the co-release of glutamate and PACAP in the hypothalamus (Lindberg et al, submitted for publication to Frontiers in Neuroscience). We have also learned that pituitary adenylate cyclase-activating polypeptide (PACAP) is co-expressed with either glutamate or GABA (based on vesicular transporter markers for these two neurotransmitter systems) in neurons throughout the brain, and that PACAP neurons in stress-associated nuclei of the brain are glutamatergic. We have adopted the working hypothesis, based on our work in the retinohypothalamic system with glutamate and PACAP, and in vasopressinergic/glutamatergic projections to locus coeruleus as well as habenula and amygdala, that the post-synaptic actions of PACAP and vasopressin may require glutamate co-release (or that the post-synaptic actions of glutamate may require co-transmission of these neuropeptides). We are exploring a second working hypothesis, that Gs-coupled receptors for catecholamines and neuropeptides exert important post-synaptic actions related to encoding of experience through neuronal plasticity, via signaling to the MAP kinase ERK via the neuron-specific cyclic AMP effector NCS-Rapgef2, and that these effects are independent of the cellular effects of activation of the canonical cyclic AMP effector protein kinase A (PKA). In the course of the year, we have adduced, and are preparing for publication, evidence that in a specific class of dopaminoceptive neurons of the nucleus accumbens (D1 dopaminoceptive neurons), NCS-Rapgef2 is the critical link between cyclic AMP elevation and activation of ERK, and subsequently, a specific cohort of ERK-inducible genes that mediate stable functional changes in these neurons that drive cocaine-seeking behavior. We continue to search for the behavioral substrate of NCS-Rapgef2-dependent activation of ERK at PACAPergic synapses. The significance of this work is that if the NCS-Rapgef2-dependent activation of ERK represents a specific pathway for experience-dependent stable changes in neuronal function (neuronal plasticity), a pharmacological approach with this molecular as its target may be worthy of further development. Such an approach may lead to development of a compound with effects on learned behaviors that are more conditional, and therefore more specific, than other targets that are closer to the post-synapse, and therefore less parcellated for function, and less specific.